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Klotho converts canonical FGF receptor into a specific receptor for FGF23

Nature volume 444, pages 770–774 (2006)Cite this article

Abstract

FGF23 is a unique member of the fibroblast growth factor (FGF) family because it acts as a hormone that derives from bone and regulates kidney functions, whereas most other family members are thought to regulate various cell functions at a local level1,2,3,4,5. The renotropic activity of circulating FGF23 indicates the possible presence of an FGF23-specific receptor in the kidney6. Here we show that a previously undescribed receptor conversion by Klotho, a senescence-related molecule7, generates the FGF23 receptor. Using a renal homogenate, we found that Klotho binds to FGF23. Forced expression of Klotho enabled the high-affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wild-type mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signalling, we searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. These findings provide insights into the diversity and specificity of interactions between FGF and FGF receptors.

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Figure 1: Egr-1 expression and ERK phosphorylation induced by FGF23 in vivo.
Figure 2: FGF23 binds to Klotho and evokes cellular responses in Klotho-expressing cells.
Figure 3: An anti-Klotho monoclonal antibody antagonizes FGF23 both in vitro and in vivo.
Figure 4: Identification of FGFR1(IIIc) as a molecule that interacts with Klotho and is essential for FGF23 signalling.

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Acknowledgements

We thank R. Imai, J. Murakami, M. Sato-Fujisawa, R. Hino, K. Sakuma, K. Ono and N. Yoshii for technical assistance, and Y. Nabeshima, T. Yoneya, T. Muto, T. Kawata, Y. Aono, J. Yasutake, N. Kasai and other members of our laboratories for advice and discussion. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and from the Ministry of Health, Labour, and Welfare, Japan.

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Authors and Affiliations

  1. Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd, 3 Miyahara, Takasaki, Gunma, 370-1295, Japan

    Itaru Urakawa, Yuji Yamazaki, Takashi Shimada, Kousuke Iijima, Hisashi Hasegawa, Katsuya Okawa & Takeyoshi Yamashita

  2. Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Toshiro Fujita & Seiji Fukumoto

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  1. Itaru Urakawa
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Correspondence to Itaru Urakawa.

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Supplementary information

Supplementary Figure 1

Schematic illustration of the proposed FGF23-specific receptor that is composed of Klotho and FGFR1(IIIc). (PDF 230 kb)

Supplementary Figure 2

The specific binding of FGF23 generated by Klotho. (PDF 274 kb)

Supplementary Figure 3

Egr-1 protein was induced by FGF23 in Klotho-expressing Peak rapid cells. (PDF 138 kb)

Supplementary Figure 4

Klotho-dependent Egr-1 reporter activation by diluted serum samples from Klotho deficient mice. (PDF 142 kb)

Supplementary Figure 5

The FGFR1(IIIc)-Fc fusion protein specifically decreases FGF23 induced luciferase activity of the Egr-1 reporter. (PDF 146 kb)

Supplementary Figure 6

Effects of GAGs on the FGF23 action. (PDF 242 kb)

Supplementary Discussion

This file contains an additional discussion of the findings of this paper. (DOC 31 kb)

Supplementary Tables

This file contains Supplementary Tables 1–4. (DOC 74 kb)

Supplementary Methods

This file contains additional details on the methods used in this study. (DOC 42 kb)

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Urakawa, I., Yamazaki, Y., Shimada, T. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006). https://doi.org/10.1038/nature05315

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